Simvastatin reduces secondary brain injury caused by cortical contusion in rats: Possible involvement of TLR4/NF-κB pathway

Simvastatin, a cholesterol-lowering agent, has demonstrated neuroprotective effects against brain injury, but the underlying mechanisms remain unclear. This study was undertaken to evaluate the effect of simvastatin on the Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-kappa B) related signaling pathway and secondary brain injury in rats after traumatic brain injury (TBI). Adult male Wistar rats were divided into four groups: (1) Sham group (n=25); (2) Sham+vehicle group (n=25): (3) TBI+vehicle group (n=30): and (4) TBI+simvastatin group (n=30). Right parietal cortical contusion was made by using a weight-dropping method. In TBI+simvastatin group, simvastatin was administered orally at a dose of 37.5 mg/kg at 1 and 6 h after TBI. Brain samples were extracted at 24 h after trauma. As a result, we found that treatment with simvastatin markedly inhibited the mRNA and protein expressions of TLR4, NF-kappa B and the downstream inflammatory agents, such as interleukin-1 beta (IL-beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6(IL-6),and intercellular adhesion molecule-1 (ICAM-1). Administration of simvastatin following TBI significantly ameliorated the secondary brain damage, such as cortical apoptosis, brain edema, blood-brain barrier (BBB) impairment, and motor deficits. In conclusion, post-TBI simvastatin administration may attenuate TLR4/NF-kappa B-mediated inflammatory response in the injured rat brain, and this may be one mechanism by which simvastatin improves outcome following TBI. (c) 2009 Elsevier Inc. All rights reserved.